Biological psychiatry global open science最新文献

{"title":"Behavioral and Prefrontal Circuit Deficits in a Newly Developed Setbp1 Haploinsufficiency Mouse Model","authors":"MacKenzie A. Howard,&nbsp;Mendee A. Geist,&nbsp;Gregory J. Ordemann,&nbsp;Alena Kizimenko,&nbsp;Dominic M. Balice,&nbsp;F. Isaac Guillén,&nbsp;Emmanuella Bassey,&nbsp;Polina Lyuboslavsky,&nbsp;Audrey C. Brumback","doi":"10.1016/j.bpsgos.2025.100666","DOIUrl":"10.1016/j.bpsgos.2025.100666","url":null,"abstract":"<div><h3>Background</h3><div>SET binding protein 1 (<em>SETBP1</em>) regulates the cell cycle, gene transcription, and other vital intracellular processes. <em>SETBP1</em> loss-of-function variants cause the neurodevelopmental disorders <em>SETBP1</em>-haploinsufficiency disorder and <em>SETBP1</em>-related disorders (<em>SETBP1</em>-HD and <em>SETBP1</em>-RD), which are characterized by attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability/developmental delay, and other neurological disabilities. Here we sought to characterize behavioral, physiological, and cell morphology phenotypes of a newly developed mouse model of <em>SETBP1</em>-HD.</div></div><div><h3>Methods</h3><div>We used open field, 3-chamber, and Y-maze behavioral tests to measure activity, social interest, and spatial learning, respectively. We used whole-cell current clamp recordings from medial prefrontal cortex (mPFC) layer-5 extratelencephalic projection neurons in ex vivo slices to measure cell intrinsic and spike properties. We used morphological reconstruction to measure dendritic arborization in recorded neurons.</div></div><div><h3>Results</h3><div><em>Setbp1</em>^{<em>+/−</em>} mice exhibited hyperactivity, decreased social interest, and increased olfactory exploration in behavioral tests. Ex vivo electrophysiology revealed hypoexcitability in layer-5 extratelencephalic projection neurons in the mPFC. Morphological reconstruction revealed changes to the way branch points and length are distributed within the apical dendritic arbor of these prefrontal pyramidal neurons without changes in overall length or branch number.</div></div><div><h3>Conclusions</h3><div>These data show that <em>Setbp1</em>^{<em>+/−</em>} mice exhibit phenotypes parallel to the ADHD and ASD that are common in patients with <em>SETBP1</em>-HD. Additionally, we identified cellular changes to a key control center for attention, social behavior, and cognitive function that may elucidate the mechanism that underlies the neuropsychiatric disabilities of this disorder.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100666"},"PeriodicalIF":3.7,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"μ Opioid Modulation of Sensorimotor Functional Connectivity in Autism: Insights From a Pharmacological Neuroimaging Investigation Using Tianeptine","authors":"Mihail Dimitrov ,&nbsp;Nichol M.L. Wong ,&nbsp;Sydney Leaman ,&nbsp;Lucas G.S. França ,&nbsp;Ioannis Valasakis ,&nbsp;Jason He ,&nbsp;David J. Lythgoe ,&nbsp;James L. Findon ,&nbsp;Robert H. Wichers ,&nbsp;Vladimira Stoencheva ,&nbsp;Dene M. Robertson ,&nbsp;Sarah Blainey ,&nbsp;Glynis Ivin ,&nbsp;Štefan Holiga ,&nbsp;Mark D. Tricklebank ,&nbsp;Dafnis Batalle ,&nbsp;Declan G.M. Murphy ,&nbsp;Gráinne M. McAlonan ,&nbsp;Eileen Daly","doi":"10.1016/j.bpsgos.2025.100663","DOIUrl":"10.1016/j.bpsgos.2025.100663","url":null,"abstract":"<div><h3>Background</h3><div>Reproducible patterns of atypical functional connectivity (FC) of sensorimotor and higher-order networks have previously been identified in the autistic brain. However, the neurosignaling pathways underpinning these differences remain unclear. The μ opioid system is involved in sensory processing as well as social and reward behaviors and has been implicated in autism, suggesting a potential role in shaping the autistic brain. Therefore, we tested the hypothesis that there is atypical involvement of the μ opioid system in these networks in autism.</div></div><div><h3>Methods</h3><div>We used a placebo-controlled, double-blind, randomized, crossover study design to compare the effects of a single dose of the μ opioid receptor agonist tianeptine in autistic (<em>n</em> = 20) and nonautistic (<em>n</em> = 21) males on FC of sensorimotor and frontoparietal networks.</div></div><div><h3>Results</h3><div>We found that tianeptine increased FC of a sensorimotor network previously characterized by atypically low FC in autism. The connectivity of the frontoparietal network was not significantly shifted.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that μ opioid neurosignaling may contribute to functional brain differences in the sensorimotor network in autism. Given that sensorimotor system alterations are thought to be central to autism and contribute to other core autistic features, as well as adaptability and mental health, further research is warranted to explore the translational potential of μ opioid modulation in autism.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100663"},"PeriodicalIF":3.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Brain Activity Associated With Intermittent Rhythmic Delta/Theta Activity: A Transdiagnostic Electroencephalography–Functional Magnetic Resonance Imaging Resting-State Study","authors":"Bernd Feige ,&nbsp;Katharina von Zedtwitz ,&nbsp;Isabelle Matteit ,&nbsp;Andrea Schlump ,&nbsp;Volker A. Coenen ,&nbsp;Kathrin Nickel ,&nbsp;Kimon Runge ,&nbsp;Harald Prüss ,&nbsp;Alexander Rau ,&nbsp;Marco Reisert ,&nbsp;Swantje Matthies ,&nbsp;Katharina Domschke ,&nbsp;Simon J. Maier ,&nbsp;Ludger Tebartz van Elst ,&nbsp;Dominique Endres","doi":"10.1016/j.bpsgos.2025.100661","DOIUrl":"10.1016/j.bpsgos.2025.100661","url":null,"abstract":"<div><h3>Background</h3><div>Intermittent rhythmic delta/theta activity (IRDA/IRTA) detected via electroencephalography (EEG) has been implicated in the pathophysiology of neuropsychiatric illnesses. Therefore, a combined EEG and functional magnetic resonance imaging (fMRI) approach was applied in a transdiagnostic group of patients with different causalities, i.e., autoimmune-mediated (in suspected autoimmune psychiatric syndromes [APS]) and primary psychiatric (borderline personality disorder [BPD]) causalities, as well as in healthy control (HC) participants, to characterize the brain regions functionally correlated with IRDA/IRTA.</div></div><div><h3>Methods</h3><div>Overall, 135 EEG-fMRI datasets met the quality criteria, including 33 patients with suspected APS, 59 cases with BPD, and 43 HC participants. fMRI data were obtained using ultrafast MR encephalography and analyzed using AFNI. IRDA/IRTA events were separated from artifacts using independent component analysis and detected algorithmically. Brain regions (clusters) significantly correlated with IRDA/IRTA were first determined in all participants. Clusters occurring across all groups were classified as consensus areas. The groups were also analyzed individually, adding disease- or disorder-specific clusters not overlapping with the consensus areas.</div></div><div><h3>Results</h3><div>Eleven consensus areas were identified across the 3 groups: 5 of them showed increased activity (Brodmann area [BA] 43-right [r], BA 2-left [l], BA 4-r, BA 18-r, BA 26/29/30-r), and 6 had reduced activity (BA 39-l, BA 10-l, BA 23-l, BA 19-l, BA 10-r, BA 18-l). The APS group showed 5 additional clusters, all with reduced activity (BAs 39-r, 1/3-r, 8-r, 4-l, 21-r). The BPD group showed one further cluster with increased activity (BA 17-l).</div></div><div><h3>Conclusions</h3><div>In this study, IRDA/IRTA-related brain activity changes across the groups were identified, with excitatory brain activity especially in fronto-centro-temporal brain areas with similarities to the salience network. Additional disease- or disorder-specific changes were discovered in APS and BPD.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100661"},"PeriodicalIF":3.7,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-Based Electroencephalography Phenotyping Uncovers Distinct Neurocomputational Mechanisms Underlying Learning Impairments Across Psychopathologies","authors":"Nadja R. Ging-Jehli ,&nbsp;Rachel Rac-Lubashevsky ,&nbsp;Krishn Bera ,&nbsp;Megan A. Boudewyn ,&nbsp;Cameron S. Carter ,&nbsp;Molly A. Erickson ,&nbsp;James M. Gold ,&nbsp;Steven J. Luck ,&nbsp;J. Daniel Ragland ,&nbsp;Andrew P. Yonelinas ,&nbsp;Angus W. MacDonald III ,&nbsp;Deanna M. Barch ,&nbsp;Michael J. Frank","doi":"10.1016/j.bpsgos.2025.100660","DOIUrl":"10.1016/j.bpsgos.2025.100660","url":null,"abstract":"<div><h3>Background</h3><div>Major depressive disorder (MDD), bipolar disorder (BP), and schizophrenia (SCZ) involve learning impairments with poorly understood mechanisms. Understanding both the similarities and differences in these mechanisms is important to guide the development of new, targeted interventions.</div></div><div><h3>Methods</h3><div>A total of 255 participants diagnosed with MDD (<em>n</em> = 54), BP (<em>n</em> = 47), or SCZ (<em>n</em> = 67) or without any clinical diagnoses (control [CTRL]) (<em>n</em> = 87) performed an associative learning task. Computational modeling quantified the mechanistic interplay between working memory (WM) and reinforcement learning (RL). The latent RL and WM signatures in the electroencephalography (EEG) dynamics showed shared and distinct neurocognitive mechanisms underlying learning.</div></div><div><h3>Results</h3><div>All clinical groups showed learning impairments at the behavioral level. Model-based EEG analyses linked these impairments to distinct patterns in the dynamic interplay between latent RL and WM mechanisms, contrasting with the typical patterns observed in the CTRL group. SCZ was characterized by reduced neural markers of WM, weakening the cooperative influence of WM onto RL (reduced WM recruitment), and reduced integration of negative feedback. Conversely, MDD was characterized by reduced reciprocal influence of RL onto WM, reducing the tendency to upregulate WM contribution with reward history (impaired WM management). Finally, BP was characterized by deficits in both WM and RL recruitment, along with higher WM decay.</div></div><div><h3>Conclusions</h3><div>Behavioral learning impairments that seem similar across clinical groups can be linked to distinct neurocognitive mechanisms via integrative neurocomputational modeling. Our approach provides insights into the interplay of underlying learning mechanisms and how they manifest differently across psychopathologies.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100660"},"PeriodicalIF":3.7,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucagon-Like Peptide-1 Receptor Agonists and Alcohol Use: A Real-Word Observational Study in a Large, Integrated Health Care System","authors":"Vanessa A. Palzes ,&nbsp;Brianna Costales ,&nbsp;Stacy Sterling ,&nbsp;Andrea Kline-Simon ,&nbsp;Lorenzo Leggio ,&nbsp;Mehdi Farokhnia","doi":"10.1016/j.bpsgos.2025.100659","DOIUrl":"10.1016/j.bpsgos.2025.100659","url":null,"abstract":"<div><h3>Background</h3><div>Growing research suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce alcohol consumption, positioning them as new potential pharmacotherapies for alcohol use disorder. However, human studies examining alcohol consumption measures in generalizable samples have been limited.</div></div><div><h3>Methods</h3><div>In this cohort study, we analyzed electronic health records from a large, integrated health care system (Kaiser Permanente Northern California) to examine the association between new prescriptions of GLP-1RAs and change in alcohol use among adults. Propensity score matching was utilized to account for differences in baseline characteristics between GLP-1RA–treated (<em>n</em> = 1214) and untreated (<em>n</em> = 1063) individuals. Changes in average drinks consumed per week (drinks/week) from baseline to follow-up (up to 1 year) were compared between groups using difference-in-differences (D-I-D) analysis. Stratified analyses examined treatment effect variation by sex, obesity, and baseline alcohol use risk level.</div></div><div><h3>Results</h3><div>Both GLP1-RA–treated and untreated groups reduced their drinks/week from baseline to follow-up (mean change [95% CI] = −1.81 [−2.11 to −1.51] and −1.38 [−1.70 to −1.06], respectively); the group difference did not reach statistical significance (D-I-D [95% CI] = −0.43 [−0.87 to 0.01]). Among individuals with low-risk baseline alcohol use, including 1126 (92.8%) GLP-1RA–treated and 996 (93.7%) untreated individuals, receipt of GLP-1RAs was associated with significantly greater reductions in drinks/week (D-I-D [95% CI] = −0.32 [−0.64 to −0.01]). Treatment effects did not vary by sex or obesity.</div></div><div><h3>Conclusions</h3><div>GLP-1RAs may be effective in reducing average weekly alcohol consumption, even in individuals with low-risk use. The small subsample of individuals with high-risk use limited our ability to estimate associations in this group.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100659"},"PeriodicalIF":3.7,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress History Modulates Corticotropin-Releasing Factor Neurons to Establish Resilience","authors":"Sherod E. Haynes ,&nbsp;Anthony Lacagnina ,&nbsp;Hyun Seong Seo ,&nbsp;Fang Li ,&nbsp;Xiao Yang ,&nbsp;Muhammad Furqan Afzal ,&nbsp;Carole Morel ,&nbsp;Aurelie Menigoz ,&nbsp;Kanaka Rajan ,&nbsp;Roger L. Clem ,&nbsp;Barbara Juarez ,&nbsp;Helen S. Mayberg ,&nbsp;Donald G. Rainnie ,&nbsp;Larry J. Young ,&nbsp;Ming-Hu Han","doi":"10.1016/j.bpsgos.2025.100656","DOIUrl":"10.1016/j.bpsgos.2025.100656","url":null,"abstract":"<div><h3>Background</h3><div>Cumulative stress is a major risk factor for developing major depressive disorder (MDD), but not everyone experiencing chronic stress develops MDD. In those who do not, it is unclear at what point or by what mechanism a trajectory of stable resiliency emerges.</div></div><div><h3>Methods</h3><div>Utilizing a 10-day repeated social defeat stress (RSDS) model for MDD, we observed that a critical period between 7 and 10 daily defeats marks the phenotypical divergence of resilient from susceptible male mice. Cell-type selective electrophysiology, chemogenetics, optogenetics, and RNA quantification were used to investigate the nature of stress effects on neuroadaptation in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) required to determine resilience.</div></div><div><h3>Results</h3><div>In response to ongoing stress, corticotropin-releasing factor (CRF⁺, but not CRF⁻) neurons of the BNSTov displayed a sustained increased firing rate in resilient but not susceptible mice. This neurophysiological adaptation was self-sustaining, but only after 7 critical stress exposures, indicating that the process of developing resilience is dependent on stress history.</div></div><div><h3>Conclusions</h3><div>Our study reveals a novel process by which individuals may persist in the face of adversity by way of stress-provoked activation, not inhibition of a key CRF limbic region that establishes a pathway to resilience.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100656"},"PeriodicalIF":3.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial Intelligence Meets Ultra-High-Field Neuroimaging to Examine Psychosis","authors":"Deepak K. Sarpal","doi":"10.1016/j.bpsgos.2025.100641","DOIUrl":"10.1016/j.bpsgos.2025.100641","url":null,"abstract":"","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 1","pages":"Article 100641"},"PeriodicalIF":3.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain State Dynamics in Ketamine-Induced Dissociation Resemble Those in Posttraumatic Stress Disorder","authors":"Noam Goldway ,&nbsp;Taly Markovits ,&nbsp;Naomi Fine ,&nbsp;Tom Fruchtman-Steinbok ,&nbsp;Guy Gurevitch ,&nbsp;Gustavo Deco ,&nbsp;Haggai Sharon ,&nbsp;Talma Hendler","doi":"10.1016/j.bpsgos.2025.100655","DOIUrl":"10.1016/j.bpsgos.2025.100655","url":null,"abstract":"<div><h3>Background</h3><div>Dissociation, an altered state of consciousness in which individuals feel detached from their body, environment, and sense of self, is a common feature of posttraumatic stress disorder (PTSD). Despite its significance, the neurocognitive processes underlying dissociation remain poorly understood, potentially limiting diagnostic precision and treatment efficacy in PTSD.</div></div><div><h3>Methods</h3><div>To address this gap, we applied network control theory to resting-state functional magnetic resonance imaging to examine neural dynamics during dissociative states in 2 contexts: healthy volunteers (<em>n</em> = 30) undergoing intravenous administration of ketamine, an anesthetic known to induce dissociative states, and patients with PTSD receiving an intervention aimed at alleviating dissociative symptoms (a secondary analysis of data from 78 patients who participated in previously conducted clinical trials).</div></div><div><h3>Results</h3><div>Ketamine administration led to resting-state brain dynamics resembling those observed in patients with PTSD before treatment, characterized by an increased dominance of a default mode network (DMN) meta-state and a decreased dominance of a somatomotor network (SOM) meta-state. Posttreatment reduction in the dominance of the DMN meta-state correlated with a decrease in dissociative symptoms in patients with PTSD. Computational modeling analysis revealed that after treatment, patients with PTSD exhibited a more organized and less entropic brain state. However, contrary to our hypothesis, ketamine administration did not lead to significant changes in these entropy-related indices.</div></div><div><h3>Conclusions</h3><div>Dissociative states, whether induced by pharmacological manipulation or clinical condition, are accompanied by increased dominance of the DMN meta-state and reduced dominance of the SOM meta-state.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100655"},"PeriodicalIF":3.7,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing Analysis of Individual Differences in Behavior to Identify Novel Mechanisms Relevant to Neuropsychiatric Disorders","authors":"Mary M. Torregrossa","doi":"10.1016/j.bpsgos.2025.100639","DOIUrl":"10.1016/j.bpsgos.2025.100639","url":null,"abstract":"","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 1","pages":"Article 100639"},"PeriodicalIF":3.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Specific Associations of Irritability With Subcortical Brain Volumes","authors":"Mariah DeSerisy ,&nbsp;Huiyu Yang ,&nbsp;Jacob W. Cohen ,&nbsp;Juan Sanchez-Peña ,&nbsp;David Semanek ,&nbsp;Hajer Nakua ,&nbsp;Gaurav H. Patel ,&nbsp;David Pagliaccio ,&nbsp;Amy E. Margolis","doi":"10.1016/j.bpsgos.2025.100653","DOIUrl":"10.1016/j.bpsgos.2025.100653","url":null,"abstract":"<div><h3>Background</h3><div>Irritability is transdiagnostic and associated with considerable impairment. The behavioral presentation of irritability may vary with age, sex, and diagnosis. Although inconsistent, clinical evidence indicates that irritability may present as temper tantrums associated with neurodevelopmental disorders in young boys, whereas irritability in girls may manifest in adolescence associated with negative mood. Functional activation of subcortical regions is characteristic of irritability, but the structural correlates of irritability in these regions are underexplored. We hypothesized that age, sex, and diagnosis would modify subcortical correlates of irritability.</div></div><div><h3>Methods</h3><div>False discovery rate–corrected regression models tested whether associations between irritability and subcortical structures were moderated by sex, age, or diagnosis in 1792 youths from the Healthy Brain Network dataset (release 11.0), a cohort weighted for psychiatric problems. Irritability was measured via the Affective Reactivity Index. FreeSurfer 6.0.1 extracted subcortical structures.</div></div><div><h3>Results</h3><div>Effect modification by sex indicated higher irritability associated with smaller reward-related volumes (right nucleus accumbens, bilateral caudate) in boys and with larger threat-related volumes (left amygdala) in girls. Effect modification by age or diagnosis was not significant.</div></div><div><h3>Conclusions</h3><div>Sex-specific subcortical correlates may explain sex-specific differences in the behavioral presentation of irritability. In models of irritability, the subcortex governs initiation of angry responses, which are dampened by prefrontal cortices. The altered volumes in reward-related regions in boys and threat-related regions in girls reported herein may be markers of early risk for irritability and/or possible targets for brain-informed interventions. Girls may benefit from irritability treatments targeting threat-based pathways, and boys may benefit from treatments targeting reward-based pathways.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"6 2","pages":"Article 100653"},"PeriodicalIF":3.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}